Sodium channel blockers play key roles in a large number of functions related to the body. In addition to the naturally produced sodium channel blockers produced in the body, a variety of non-naturally occurring drugs are utilized to block sodium channels from the intracellular side of the channel. For example, local anesthetics are non-selective sodium channel blockers that fail to discriminate between sodium channel activity required for normal ongoing sensation and similar activity involved in nociceptor signaling. There are, however, useful in pain relief in numerous applications, but suffer from the drawback of undesired blockade of motor function.
The sodium channel is also implicated in conditions of the bladder, e.g., interstitial cystitis (IC—bladder pain along with increased urinary frequency; also known as painful bladder syndrome) and overactive bladder (OAB—bladder storage issues such as urgency, frequency and nocturia). OAB presents as an increased voiding frequency and may be the result of infection or injury to the bladder tissue itself, e.g., interstitial cystitis, or may arise as a comorbid association to conditions such as stress, anxiety disorder, endometriosis, vulvodynia, chronic fatigue syndrome, or fibromyalgia, among other conditions. In both IC and OAB, increased afferent signals are conducted by myelinated Aδ-fibers and the unmyelinated C-fibers. Typically the C-fibers mediate painful mechanical, thermal and chemical sensations and this signaling requires action potentials that are initiated and maintained via activated sodium channels. Therefore, targeting the sodium channel mediated conduction of action potentials in bladder C-fiber afferent nerves may be a therapeutic approach for the treatment of OAB and IC (Steers, 2002, Rev. Urol., 4 Suppl 4:S7-S18). In an animal model of IC and OAB, blocking the conduction of afferent signals with the sodium channel blocker lidocaine, normalizes the micturition pattern as determined by cystometry (Juszczak, 2009, J. Physiol. Pharmacol. December, 60(4):85-91). Similarly, mexilitine prevents the painful sensation of noxious urinary bladder distention (Su, 2008, Neurourol. Urodyn., 27(3):249-53). Unfortunately neither lidocaine nor mexilitine offer therapeutically tractable options for patients with these bladder conditions due to the fact that their beneficial effects are short-lived.
The cationic sodium channel blocker, QX-314, selectively blocks sodium channel activity in nociceptor neurons when administered in the presence of capsaicin, an agonist for the transient receptor potential cation channel, subfamily V, member 1 (TRPV1). TRPV1 is preferentially expressed peripherally in small-diameter primary afferent nociceptors and is up-regulated in chronic pain states. However, TRPV1 is not present in the large diameter afferent neurons that convey tactile sensations nor is TRPV1 present in motor neuron efferent fibers.
QX-314 is the N-methylated analog of lidocaine and bears a permanent positive charge. It is unable to cross the neuronal cell membrane when applied externally and has no effect on neuronal sodium-channel activity unless afforded access, to the cell cytoplasm, through open TRPV1 channels in which case it causes prolonged block of sodium-channel activity. Voltage-clamp single cell electrophysiology experiments illustrated that QX-314 permeates through capsaicin-activated TRPV1 channels and blocks sodium channel activity. In vivo, perisciatic administration of a QX-314/capsaicin combination produced pronounced and long-lasting nociceptor-selective nerve blockade.

The in vitro apparent affinity (IC50) of QX-314 for blocking sodium current in DRG neurons (when co-applied with 1 μM capsaicin and measured using the whole-cell voltage clamp approach) is modest at 30 μM.
There remains a need in the art for new and novel cationic sodium channel blockers with more potent activity than QX-314 in vitro and longer duration of action in vivo when utilized alone or co-administered with appropriate TRPV1 stimuli.